Phosphorothioate modified antisense oligonucleotides (ASOs) have been designed complementary to various regulatory and structural genes of HIV-1. These ASOs are being evaluated for their anti-HIV activity using H9 and U937 cells as target cells. Antiviral activity is being assessed by p24 antigen and PCR. Preliminary results suggest that ASOs from the tat and the LTR regions were most effective in inhibiting virus expression. These ASOs are being packaged into liposomes and administered either singly or in combination with other ASOs or with AZT to target cells and their antiviral activity evaluated. Similar experiments are being performed with HIV-2. Oligonucleotides that allow the formation of ribozyme complexes or that interact with b-ribbon motifs on DNA are also being evaluated for their antiviral activity against HIV-1 and HIV-2.